Oxidative free-radical cyclization, in which the initial radical is generated oxidatively and/or the cyclic radical is oxidized to terminate the reaction, has considerable synthetic potential since more highly functionalized products can be prepared from simpler precursors than with the standard tin hydride reductive radical cyclizations. The goal of this research is to develop oxidative free-radical cyclization into a reliable and versatile method for the synthesis of highly functionalized cyclic and polycyclic compounds. This proposal consists of several interrelated studies developing new synthetic methods based on, and examining the mechanism of, oxidative free-radical cyclization using Mn(III), Cu(II) or Ce(IV) as the oxidant, and several natural product syntheses designed to exploit and develop oxidative free-radical cyclization. In the area of methods development we plan to examine: (1) addition to alkynes, solvent effects, (2) use of haloalkenes to control the regiochemistry of the cyclization, (3) new substitution patterns, (4) trapping by addition to nitriles, (5) trapping by addition to aldehydes, (6) oxidation, cyclization, oxidation, cyclization, (7) oxidative cyclization followed by intermolecular trapping, (8) oxidation, cyclization, allylation, oxidation and cyclization, (9) use of conjugated beta-keto esters, (10) use of sulfoxides for asymmetric free-radical cyclization, (11) probes for the reversibility of radical cyclization, (12) oxidative cyclization of unsaturated silyl enol ethers, (13) oxidative cyclization of unsaturated silyloxycyclopropanes, and (14) conversion of other radicals to alkenes with copper carboxylates. In the area of total synthesis we plan to carry out syntheses of: (1) velloziolone, (2) a key tricyclic intermediate for gibberellic acid synthesis, (3) steviol, (4) iresin, (5) avenaciolide, and (6) models for aklavinone synthesis. The focus of this work is the development of new synthetic methodology that will be broadly applicable in the synthesis of a wide variety biologically active compounds. Results obtained to date suggest that oxidative free-radical cyclization will be an important new method applicable to the preparation of a wide variety of highly functionalized cyclic and polycyclic targets. The methods and syntheses projects have been designed to lead to increased mechanistic understanding of free-radical chemistry and develop new applications of oxidative free-radical cyclizations.